Compounds that exhibit biological activity typically contain at least one asymmetric carbon atom, i.e., at least one choral center. A particular stereoisomer of such a compound usually exhibits excellent biological activity, whereas the other stereoisomers exhibit no or little biological activity. Accordingly, investigators strive to synthesize the biologically active stereoisomer, while minimizing or eliminating synthesis of the inactive or less active stereoisomer.
Stereochemical purity is important in the pharmaceutical field, where many of the most often prescribed drugs exhibit chirality. For example, the L-enantiomer of the β-adrenergic blocking agent, propranolol, is known to be 100 times more potent than its D-enantiomer. Additionally, optical purity is important in the pharmaceutical field because certain stereoisomers impart a deleterious effect, rather than an advantageous or inert effect. For example, it is believed that the D-enantiomer of thalidomide is a safe and effective sedative when prescribed for the control of morning sickness during pregnancy, whereas its corresponding L-enantiomer is believed to be a potent teratogen.
A stereoselective synthesis, therefore, permits the preparation of a more useful drug product. For example, the administered dose of a drug can be reduced because only the active stereoisomer is administered to at individual, as opposed to a mixture which contains a large amount of inactive stereoisomer. This reduced dose of active stereoisomer also reduces adverse side effects compared to a dose containing a mixture of stereoisomers. In addition, a stereoselective synthesis is more economical because a step of separating the desired stereoisomer from the undesired stereoisomer is simplified or eliminated, and raw material wastes and costs are decreased because reactants are not consumed in the synthesis of undesired stereoisomers.
Many biologically active compounds contain two asymmetric carbon atoms, i.e., two stereogenic centers, wherein each asymmetric carbon atom is a member of a ring system and each is bonded to a hydrogen atom and to a substituent different from a hydrogen atom. The nonhydrogen substituents of the asymmetric carbon atoms therefore can be in a cis or a trans configuration. A particularly difficult problem encountered in the synthesis of such biologically active compounds is the high yield and high purity preparation of a particular stereoisomer, i.e., the desired diastereomer, wherein the nonhydrogen substituents of the asymmetric carbon atoms are in the cis configuration, or the trans configuration, depending upon which diastereomer is the more biologically active.
For such compounds, it is necessary to provide a synthetic pathway that provides each stereogenic center of correct stereochemistry, and thereby yield the desired diastereomer. The synthetic pathway also should provide a high yield of the desired diastereomer in as few steps as possible, with a minimum of diastereomer separation and purification.
For example, U.S. Pat. No. 5,859,006, incorporated herein by reference, discloses the synthesis of (6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione having a structure (I):
Compound (I) has two asymmetric carbon atoms, each denoted by an asterisk, wherein the nonhydrogen substituents of the asymmetric-carbon atoms are in the cis configuration. Compound (I) can be prepared by the two synthetic pathways disclosed in U.S. Pat. No. 5,859,006. Compound (I) is a potent and selective inhibitor of the phosphodiesterase enzyme PDE5, and has various therapeutic uses, for example, the treatment of male erectile dysfunction.
The first synthetic pathway (A), from D-tryptophan, has few steps, but the yield of the desired diastereomer (i.e., Compound II) is poor and requires a separation step from the trans-stereo-isomer (Compound IIa). Pathway (A) also utilizes the highly corrosive trifluoroacetic acid (i.e., TFA or CF3CO2H). The key step in pathway A is a classic Pictet-Spengler reaction using D-tryptophan methyl ester and piperonal to yield substituted tetrahydro-β-carboline Compounds (II) and (IIa). The second pathway (B) provides a better yield of the desired Compound I, but requires numerous synthetic steps. In each synthetic pathway, the key intermediate in the synthesis of Compound (I) is Compound (II). Compound (I) then is synthesized from Compound (II) in two straightforward synthetic steps.